Emulsion systems have been used as dosage forms, normally for the oral administration of oils, or in the form of topical products or cosmetics. At the present time, emulsions also have utility as parenteral drug delivery systems. L. D. Pelham, Am. J. Hosp. Pharm., 38: 198-208 (1981), reports total parenteral nutrition (TPN) has been one of the most important advances in acute patient care over the past decade. It is a means of providing intravenous nutrition to patients who are unable to absorb nutrients via the gastrointestinal tract. Infused nutrients may include amino acids, dextrose, electrolytes, minerals, vitamins, fatty acids and trace minerals.
As reported by L. D. Pelham in the prior cited reference, intravenous fat emulsions have been commercially available in European countries for over 20 years though their use in the United States has been restricted until recently because of severe and infrequently fatal reactions as reported in the Br. J. Surg., 52: 795-800 (1965) and Drug Intell. Clin. Pharm., 6: 321-30 (1972). Lipomul.RTM., the first intravenous fat emulsion introduced in the United States, was withdrawn in 1965 following several reports of a "fat overloading syndrome" as described in the Br. J. Surg., 52: 291-8 (1965) and Metabolism 6: 815-21 (1957). Intralipid.RTM., distributed by Cutter Laboratories was approved for use in the United States in 1975, it had previously been used in Europe for years. In 1979, Liposyn.RTM., a second intravenous fat emulsion, was marketed by Abbott Laboratories.
Intralipid.RTM. and Liposyn.RTM. contain 10% w/v or 20% w/v soybean oil and 10% w/v safflower oil respectively, as a source of polyunsaturated fatty acids. Each product contains 1.2% w/v of purified egg phospholipids as an emulsifier and water is added to make a 10% w/v or 20% w/v emulsion. Until recently over 10% emulsions were available in the U.S. In Europe 20% emulsions constitute the majority of use as reported in Surg. Clin. North Am., 58: 1055-70 (1978). Glycerol, a water-soluble substance, is added to make fat emulsions isotonic, with 2.25% w/v in Intralipid.RTM. and 2.5% w/v in Liposyn.RTM.. Since fat exerts a minimal osmotic pressure, glycerol contributes twice the osmotic load as an equal weight of glucose, mannitol, or sorbitol according to the N. Engl. J. Med., 297: 1444-52 (1977). Both Intralipid.RTM. and Liposyn.RTM. have a pH range of 5.5 to 8 and emulsified fat particles in Intralipid.RTM. and Liposyn.RTM. range from 0.1 to 0.5 .mu.m in diameter, slightly smaller than endogenous chylomicrons as reported in several references, including Metabolism, 27: 1109-27 (1978).
Since the early 1970's most reports in the literature for adverse reactions attributed to fat emulsions related to the use of Intralipid.RTM. simply because it was the only commercially available fat emulsion. Similar adverse reactions may be reported for Liposyn.RTM. with the passage of time. Intralipid.RTM. and Liposyn.RTM. appear to have significantly fewer and milder adverse reactions than Lipomul.RTM. as reported in Can. Med. Assoc. J., 111: 152-4 (1974) and Liposyn.RTM. Research Conference proceedings. North Chicago; Abbott Laboratories (1979). Most serious reports today are associated with excessive doses as reported in Arch. Surg., 111: 1391-3 (1976).
Two types of adverse reactions occur with fat infusions. The first type is usually acute or mild and occurs during the infusion. The second type occurs later with prolonged use of intravenous fat emulsions. The most commonly reported acute reactions include a febrile response, chills and shivering and pain in the chest or back, described in J. Pediatr., 86: 2-16 (1975). Very rapid infusions may cause palpitations, tachypnea, sudden tightness of the chest, wheezing, cyanosis, nausea, pain at injection site, oily taste and headache as reported in Br. J. Surg., 52: 291-8 (1965). During recent years the intravenous fat emulsions which are initially reserved for the provision of essential fatty acids have gained in popularity as a caloric source as described in U.S. Pat. No. 3,169,094 and by M. T. Yeo, et al. in Arch. Surg., 106: 792-6 (1973). As reported by R. Jeppsson and S. Ljungberg in Acta Pharmacal. et. Toxical, 36: 312-20 (1975). Ljungberg and Jeppsson investigation pharmacodynamic effects of using emulsions as vehicles for lipid soluble materials in 1970, '72 and '73. Effects were investigated after parenteral administration of soybean oil emulsions containing various drugs dissolved in the oil phase. The drugs studied were barbituric acids, cyclandelate nitroglycerin and diazepam. The results indicated that the emulsion formulations would be suitable vehicles for lipid soluble drugs intended for intravascular administration, since the pharmacological effects were nearly equal to those found after a water solution of the sodium salts. A prolongation of anesthesia was observed for barbituric acids when administered in the oil phase of a soybean emulsion as compared with a solution of the corresponding sodium salt. The results were explained as a slow release of the drug from the oil particles or, the possibility of a more specific delivery of the drugs to the central nervous system when the drug is contained in oil droplets [R. Jeppsson, Acta pharmaceutica sueccia, 9, 81-90 (1972)]. A commercial diazepam product has been reported as being available by O. Dardel, et al., Anaesth. Scand., 20: 221-24 (1976). This lipid emulsion formulation was prepared by Vitrum AB, Sweden and shows many similarities to Intralipid.RTM.. The new lipid emulsion form was found to significantly reduce the incidence of local side effects involving the venous system and no significant difference in the therapeutic effect of the different preparative forms of diazepam was observed.